microorganisms

Review
Novel Antibiotics for Multidrug-Resistant
Gram-Positive Microorganisms
Despoina Koulenti 1,2, * , Elena Xu 1 , Isaac Yin Sum Mok 1,† , Andrew Song 1,† ,
Drosos E. Karageorgopoulos 3 , Apostolos Armaganidis 2 , Jeffrey Lipman 1,4,5,‡
and Sotirios Tsiodras 3,‡
1 UQ Centre for Clinical Research, Faculty of Medicine, The University of Queensland,
Brisbane, QLD 4072, Australia
2 2nd Critical Care Department, Attikon University Hospital, 12462 Athens, Greece
3 4th Department of Internal Medicine, Attikon University Hospital, 12462 Athens, Greece
4 Department of Intensive Care Medicine, Royal Brisbane and Women’s Hospital, Brisbane 4029, Australia
5 Anesthesiology and Critical Care, Centre Hospitalier Universitaire De Nîmes (CHU),
University of Montpellier, 30029 Nîmes, France
* Correspondence: d.koulenti@uq.edu.au
† Equal contribution-both 3rd authors.
‡ They are joint senior authors.




Received: 13 July 2019; Accepted: 15 August 2019; Published: 18 August 2019


Abstract: Increasing multidrug-resistance to Gram-positive pathogens, particularly to staphylococci,

enterococci and streptococci, is a major problem, resulting in significant morbidity, mortality
and healthcare costs. In recent years, only a small number of novel antibiotics effective against
Gram-positive bacteria has been approved. This review will discuss the current evidence for novel
branded antibiotics that are highly effective in the treatment of multidrug-resistant infections by
Gram-positive pathogens, namely ceftobiprole, ceftaroline, telavancin, oritavancin, dalbavancin,
tedizolid, besifloxacin, delafloxacin, ozenoxacin, and omadacycline. The mechanism of action,
pharmacokinetics, microbiological spectrum, efficacy and safety profile will be concisely presented.
As for any emerging antibiotic agent, resistance is likely to develop against these highly effective
antibiotics. Only through appropriate dosing, utilization and careful resistance development
monitoring will these novel antibiotics continue to treat Gram-positive pathogens in the future.

Keywords: multidrug-resistance; gram-positive pathogens; novel antibiotics; ceftobiprole; ceftaroline;

telavancin; oritavancin; dalbavancin; tedizolid; besifloxacin; delafloxacin; ozenoxacin; omadacycline

1. Introduction
Antibiotic resistance is increasingly becoming a global health threat associated with increased
morbidity, mortality, prolonged hospitalization and healthcare costs [1]. It is estimated that 300 million
people will die prematurely from drug resistance over the next 35 years if antibiotic resistance is not
overcome [2]. The above additionally translates into a $USD 60 to 100 trillion worth of economic
output lost by 2050 [2]. Over the past five years, a number of antimicrobial agents that are effective
against Gram-positive multidrug-resistant organisms have been developed and approved as a result
of clinical trials [3]. Most of these registrational clinical trials are done on community-acquired
infections requiring hospitalization, mainly on community-acquired pneumonia and on skin and soft
tissue infections. However, the newer agents could also play a role in the treatment of nosocomial
infections, when resistance, toxicity, drug interactions or treatment failure precludes treatment with
established agents.

Microorganisms 2019, 7, 270; doi:10.3390/microorganisms7080270 www.mdpi.com/journal/microorganisms

Microorganisms 2019, 7, 270 2 of 24

Bacterial strains with non-susceptibility to one or more antimicrobials in three or more antimicrobial
classes, are defined as multidrug-resistant (MDR) [4]. These MDR strains have been increasing at
an alarming rate over recent decades, making it more difficult, sometimes impossible, to treat common
bacterial infections with conventional antibiotics [5].
Staphylococcus aureus, the most common Gram-positive MDR pathogen causing nosocomial
infections, is a major cause of morbidity and mortality worldwide [6]. It is a frequent cause of both
hospital-acquired and community-acquired infections in both healthy individuals and patients with
risk factors or underlying conditions [6]. S. aureus can cause a wide range of infections, from mild skin
infections to life-threatening diseases, including pneumonia, osteomyelitis, sepsis and bacteremia [7].
Methicillin-resistant S. aureus (MRSA) is considered a serious threat by the Centre for Disease Control
and Prevention (CDC) and classified as high priority by the Public Health Agency of Canada (PHAC) [6].
Several studies reported that patients infected with MRSA have an elevated 30- and 90-day risk of
mortality and a 1.19-fold increase in hospital charges compared to those with methicillin-susceptible
S. aureus (MSSA) [8,9].
Another Gram-positive pathogen, Enterococcus faecium, is of particular concern due to its potential
resistance to nearly all antimicrobials currently used in medical practice [10]. It has a high propensity
to persist in the hospital environment owing to its ability to adapt to the harsh environment of
the gastrointestinal tract and flourish under antibiotic pressure [6]. As a result, it is a frequent
cause of hospital-acquired infections, such as bloodstream and urinary tract infections, which can be
detrimental in critically ill and immunocompromised patients [6]. Vancomycin-resistant E. faecium has
been classified as a serious threat by the CDC and medium-high priority by PHAC [6].
Streptococcus pneumoniae is responsible for several community-acquired infections, including
pneumonia, meningitis, acute exacerbations of chronic obstructive pulmonary disease (COPD) and
sinusitis [11]. Studies have shown certain strains of S. pneumoniae to be resistant to penicillin,
clindamycin, cotrimoxazole and erythromycin, rendering these treatment options futile [11].
CDC classified penicillin-resistant S. pneumoniae as a serious threat, whilst the PHAC classifies
it as medium-low priority [6].
This review will discuss antibiotics against Gram-positive micro-organisms approved during
the last decade, including the mechanism of action and microbiological profile as demonstrated in
in vitro and in vivo experiments, as well as dosing, safety and efficacy of the antibiotics demonstrated
in clinical trials. Targeted searches included PubMed, Google Scholar, official label information, the site
of ClinicalTrials.gov, and recent conference proceedings (of: Infectious Diseases Society of America,
European Society of Clinical Microbiology and Infectious Diseases, American Society of Microbiology).
(For novel and emerging antibiotics against Gram-negative antibiotics, we refer to another recent
review [12]).
Table 1 summarizes the novel anti-Gram-positive antibiotics approved during the last decade.
(Chemical structures summarized in Supplementary Material).
Microorganisms 2019, 7, 270 3 of 24

Table 1. Summary of novel antibiotics against Gram-positive bacteria approved by FDA and/or EMA during the last decade.

Spectrum Against
Drug Approval Time Antibiotic Class Company Indication Dose 1 Comments/Warnings 2
Organisms

Allergan Pharmaceutical • Serious anaphylactic reactions have been

Industries Ltd. ABSSSI: MRSA, MSSA, S. FDA: CABP and reported with beta-lactam antibiotics
Ceftaroline FDA: October 2010 (US/Canada); Takeda pyogenes, S. agalactiae ABSSSI 3IV: 600 mg over 5 to 60 • Direct Coombs’ test seroconversion has been
Cephalosporin reported; if anaemia develops during or after
(Teflaro/Zinforo) EMA: August 2012 Pharmaceutical Company CABP: MSSA, S. pneumoniae, EMA: CABP and min every 12 h [13]
Ltd. (Japan); Pfizer (globally H. influenzae cSSSI therapy, consider drug-induced haemolytic
except US/Canada/Japan) anaemia and ceftaroline

MRSA, ampicillin-susceptible • Serious anaphylactic reactions have been

EMA: HAP
Ceftobiprole EMA: October enterococci and IV: 500 mg over 2 h every 8 reported in patients receiving
Cephalosporin Basilea Pharmaceutica Ltd. (excluding VAP)
(Zevtera/Mabelio) 2013 penicillin-resistant h [14] beta-lactam antibiotics
and CABP
pneumococci

• Decreased efficacy with moderate/severe

pre-existing renal impairment
• Interferes with some coagulation tests e.g.,
MRSA, IV: 10 mg/kg over 60 min prothrombin time, international
Telavancin FDA: September Theravance Biopharma vancomycin-intermediate S. FDA: cSSSI, HAP every 24 h for 7–14 days normalised ratio
Lipoglycopeptide
(Vibativ) 2009 Antibiotics, Inc., aureus and penicillin-resistant (including VAP) (cSSSI) and 7–21 days • QTc prolongation
S. pneumoniae (HAP/VAP) [15] • Serious and potentially fatal
hypersensitivity reactions
• Infusion-related reactions

• Serious anaphylactic and skin reactions have

been reported with glycopeptides
Dalbavancin Durata Therapeutics MRSA, S. pyogenes, S. IV: 1000 mg over 30 min • Rapid IV glycopeptide infusion can cause
(Dalvance/ FDA: May 2014 Lipoglycopeptide (acquired by Actavis in agalactiae and E. faecalis strains FDA: ABSSSI followed one week later by upper body flushing, urticaria, pruritis
Xydalba) 2014) susceptible to vancomycin 500 mg over 30 min [16] and/or rash
• ALT elevations have been reported

• Co-administration with warfarin may

increase warfarin exposure and increase
bleeding risk
• Oritavancin administration may artificially
MSSA, MRSA, VRE and prolong aPTT for up to 48 h and prolong
Oritavancin FDA: August 2014 vancomycin-intermediate and FDA: ABSSSI IV: 1200 mg single dose over PT/INR for up to 24 h
Glycopeptide Melinta Therapeutics Inc. • Hypersensitivity and infusion related
(Orbactiv) EMA: March 2015 vancomycin-resistant EMA: ABSSSI 3 h [17]
staphylococci reactions including pruritus, urticaria and
flushing have been reported
• 4 A higher incidence of osteomyelitis

reported in the oritavancin treated ABSSSI

arm than vancomycin-treated arm
Microorganisms 2019, 7, 270 4 of 24

Table 1. Cont.

Spectrum Against
Drug Approval Time Antibiotic Class Company Indication Dose 1 Comments/Warnings 2
Organisms
Tedizolid MRSA, IV: 200 mg single dose over • Safety and efficacy not adequately evaluated
FDA: June 2014 FDA: ABSSSI
Phosphate Oxazolidinone Cubist Pharmaceuticals vancomycin-intermediate 1 h for 6 days in neutropenic patients
EMA: March 2015 EMA: ABSSSI 5 PO: 200 mg once daily [18]
(Sivextro) Enterococcus spp.

• Not for injection into the eye

Instill one drop in the • Prolonged use may result in the overgrowth
Besifloxacin MRSA, S. epidermidis, S. FDA: bacterial affected eye(s) 3 times a day, of non-susceptible organisms resulting in
FDA: June 2009 Fluoroquinolone SSP Co. Ltd. a super-infection
(Besivance) pneumoniae, and H. influenzae conjunctivitis four to 12 h apart for 7 days
[19] • Avoid contact lens wear during course
of therapy

S. aureus (including MRSA), S.

pneumoniae, other
IV: 300 mg over 1 h every 12
fluoroquinolone resistant • Hypersensitivity reactions may occur after
Delafloxacin h
FDA: June 2017 Fluoroquinolone Melinta Therapeutics Inc. strains FDA: ABSSSI first or subsequent doses
(Baxdela) PO: 450 mg tablet every 12
(Ineffective against
h for 5 to 14 days [20]
Fluoroquinolone-resistant
enterococci)

Topical: apply a thin layer • Prolonged use of ozenoxacin may result in

Ozenoxacin FDA: December Non-fluorinated MRSA, MSSA, MRSE and S. the overgrowth of non-susceptible organisms
Ferrer Internacional S.A. FDA: impetigo to the affected area twice
(Ozaenex/Xepi) 2017 quinolone pyogenes resulting in a super-infection
daily for 5 days [21]

• Commonest adverse reactions: Nausea,

Duration: 7–14 days
Loading IV Day1:
200 mg over 1 h once daily
or 100 mg over 30 min twice
MRSA, penicillin-resistant daily
and multidrug-resistant S. Maintainance:
Omadacycline FDA: CABP,
FDA: October 2018 Tetracycline Paratek Pharmaceuticals pneumoniae, and 100 mg over 30 min or 300
(Nuzyra) ABSSSI
vancomycin-resistant mg po once daily
Enterococcus spp. 6 Loading PO (ABSSSI)
Day 1&2:
450 mg once daily
Maintainance PO (ABSSSI)
300 mg once daily [22]
vomiting, hypertension, headache, diarrhea,
insomnia and constipation
• Mortality imbalance observed in the CABP
clinical trial: 8 deaths in the omadacycline
group vs. 4 in the moxifloxacin group
• Omadacycline use during tooth development
(last half of pregnancy, infancy and
childhood >8 years) may cause permanent
teeth discoloration and enamel hypoplasia
• Omadacycline use during the 2nd and 3rd
trimester of pregnancy, infancy and
childhood >8 years may cause reversible
bone growth inhibition

Notes: 1 All dosing regimens are indicated in adult patients >18 years old with no renal or hepatic impairment. See individual drug label for dosing regimens in other populations.
2 C. difficile-associated diarrhea has been reported with nearly all systemic antibacterial agents; 3 600 mg every 8 h should be considered as it is safe and is expected to be a better dosing

scheme for critically ill patients with normal or augmented renal clearance [23]. 4 Patients with ABSSSIs treated with oritavancin should be monitored closely for symptoms and signs of
osteomyelitis and in case of osteomyelitis diagnosis, appropriate treatment should be initiated promptly 5 Tedizolid has excellent oral bioavailability (more than 90%) and thus there is no
need for dosage adjustment when switching from intravenous to oral administration [24]. 6 Omadacycline per os should be administered after at a fasted state and certain foods (e.g.,
dairy products, to be avoided for at least 4 h after dosing [25].
Microorganisms 2019, 7, 270 5 of 24

2. Novel Anti-Gram-Positive Antibiotics

2.1. β-Lactams

2.1.1. Ceftaroline
Ceftaroline (trade name Zinforo under a license from Pfizer except for US, Canada and Japan;
trade name Teflaro under license by Allergan Pharmaceutical Industries Limited in US/Canada and
by Takeda Pharmaceutical Company Limited in Japan) is a novel 5th generation cephalosporin that
was approved by the Food and Drug Administration (FDA) in 2010 and from the European Medicine
Agency (EMA) in 2012 for the treatment of acute bacterial skin and skin structure infections (ABSSSIs)
and community-acquired bacterial pneumonia (CABP) [26]. Its mechanism of action involves cell wall
synthesis inhibition by inactivating penicillin-binding proteins (PBP), and it binds to PBP-1a, -2a, -2b,
and -2x proteins with a greater affinity than other penicillin and cephalosporin antibacterial drugs,
giving it enhanced activity towards MRSA and penicillin-resistant S. pneumoniae [27,28]. Ceftaroline
has bactericidal activity against a wide spectrum of Gram-positive aerobes, including MSSA, MRSA,
vancomycin-resistant S. aureus, daptomycin non-susceptible S. aureus, linezolid-resistant S. aureus,
Streptococcus pyogenes, Streptococcus agalactiae, multiple strains of resistant S. pneumoniae, while the
activity against Enterococcus faecalis (including vancomycin-resistant enterococci [VRE] strains) is
modest (not active against E. faecium) [29,30]. The antimicrobial spectrum of ceftaroline against
Gram-negative bacteria is similar to that of ceftriaxone [31].
Ceftaroline is administered by intravenous (IV) injection in a water-soluble prodrug formulation,
ceftaroline fosamil, which then undergoes in vivo conversion by plasma phosphatases almost
immediately [32]. It has a low plasma protein binding (average 20%) and a terminal half-life of
1.6 and 2.6 h after a single dose and after multiple doses, respectively [33]. Pharmacokinetic studies of
ceftaroline epithelial lining fluid (ELF) distribution among healthy adult subjects demonstrated rapid
penetration into ELF, with maximal concentrations above minimum inhibitory concentration (MIC90 )
of MRSA when given every 8 or 12 h [34]. The currently approved dosing regimen in adults with
CABP and ABSSSI are 600 mg every 12 h by IV infusion over one hour for five to seven days and five
to 14 days, respectively [13,35]. However, based on evidence of PK/PD changes of other beta-lactam
antibiotics in critically ill patients, 600 mg every 8 h should be considered as it is safe and is expected to
be a better dosing regimen for critically ill patients with normal renal function (normal or augmented
renal clearance) [23]. The pharmacokinetics of ceftaroline in pediatric patients appear similar to those
of adults; the dosing recommendations for pediatric patients are weight-based (8 mg/kg every 8 h for
2 months to younger than 2 years; 12 mg/kg every 8 h for 2 years to younger than 18 years weighing
up to 33 kg) [33]. Dosage adjustment is required in renal impairment, specifically for patients with
an estimated creatinine clearance at 50 mL/min or less [32]. Dose adjustments are made by reducing
the dose instead of the dosing interval, as the efficacy of ceftaroline is mainly determined by free-drug
concentration above MIC [36]. The commonest adverse drug events are diarrhea, nausea, and rash,
with vomiting, headache, hypokalaemia, increased liver transaminases, and phlebitis also documented
(2–3% among patients from four phase III clinical trials) [37]. Other notable adverse events with
incidence rates below 2% are bradycardia, palpitations, pyrexia, Clostridium difficile colitis, anemia,
eosinophilia, neutropenia, thrombocytopenia, and neutropenia [33]. Regarding neutropenia, it is
noteworthy that a retrospective study from US reported increased incidence after prolonged ceftaroline
exposure, namely 10–14% for ≥2 weeks and 21% ≥3 weeks of exposure, indicating the need for close
laboratory monitoring in cases of long-term administration [38].
A randomized-controlled phase III trial in adult patients with complicated skin and soft tissue
infections (cSSTIs) found that high-dose ceftaroline fosamil at 600 mg every eight hours was non-inferior
in clinical cure rates compared to vancomycin plus aztreonam (NCT01499277) [39]. It should be
mentioned that ceftaroline has not been evaluated for MRSA pneumonia in clinical trials. The relevant
registrational studies for CABP (FOCUS 1 & 2) included ceftriaxone as the comparator, which lacks
Microorganisms 2019, 7, 270 6 of 24

activity against MRSA [40]. The overall number of cases of S. aureus CABP was relatively small;
ceftaroline was effective in 18 out of 25 (72%) such cases, while ceftriaxone was effective in 15 out of 27
(55.6%), respectively [40]. The number of MDR S. pneumoniae cases was inadequate to allow for safe
conclusions [40].
An emerging concern with ceftaroline use is the reported decreased susceptibility and increased
resistance in certain MRSA clinical isolates collected around the world [36,41–43]; especially high
regional resistance percentages have been reported from China, Thailand, and Australia [36,43].
In particular, the in vitro study that evaluated MRSA isolates from Melbourne, Australia found
significant ceftaroline resistance among MDR phenotype and the CC239 strain making it a non-ideal
option for empiric treatment in suspected or known MRSA infections in regions where strain CC239
represents a significant proportion of MRSA [36]. It should be noted however, that most resistance
strains have been re-categorized as intermediate with the updated The European Committee on
Antimicrobial Susceptibility Testing (EUCAST) breakpoints [44].
A recent meta-analysis of 10 randomized control trials (RCTs) that compared the safety and
efficacy of ceftaroline versus comparators, reported a similar rate of adverse events and a significantly
lower treatment failure for ceftaroline, with pooled risk ratio (RR) 0.79 (95% CI 0.65–0.95) [45]. It should
be noted, however, that no RCTs were identified for non-complicated cSSSIs or for pneumonia other
than of CAP, that the number of cases with MRSA were few, and that there were no ICU patients
included [45]. Another recent meta-analysis that compared ceftaroline with ceftriaxone for CABP found
that both clinical efficacy and safety were similar between the two groups, while a meta-analysis that
focused on cSSSIs concluded that ceftriaxone and comparators had similar cure rates, microbiological
eradication rates and similar safety profile [46].
Ceftaroline’s spectrum of activity, efficacy and safety profile makes it a promising and attractive
addition to the available agents for the treatment of patients with sSSSIs and CABP, providing the
option of monotherapy. However, further studies are needed to assess the effectiveness of ceftaroline
in the ICU setting and for indications other than CABP and cSSSIs.

2.1.2. Ceftobiprole
Ceftobiprole (trade name Zevtera/Mabelio) is a novel 5th generation cephalosporin developed
by Basilea Pharmaceuticals. It exerts its activity by binding to PBPs, including the PBP-2a of MRSA,
and blocking bacterial cell wall synthesis [47]. It has a potent activity against a broad spectrum
of microorganisms that includes Gram-positives, such as MRSA, ampicillin-susceptible enterococci,
penicillin-resistant pneumococci and Gram-negatives; its Gram-negative spectrum is similar to that
of 3rd and 4th generation cephalosporins, i.e., not active against Gram-negative strains producing
extended-spectrum beta lactamases [47,48].
Ceftobiprole has a very low plasma protein binding (average 16%), has a half-life of approximately
3 h and is eliminated predominantly by the kidneys so dose adjustments are required for patients with
moderate to severe renal impairments [14]. In healthy volunteers, ceftobiprole demonstrated mean
and median ELF penetration percentages of 25.5% and 15.3%, respectively [49].
In two earlier randomized, multi-center, double-blind phase III trials (STRAUSS I and II) evaluating
the clinical efficacy of ceftobiprole for hospitalized patients with complicated skin and skin structure
infections (cSSSIs), ceftobiprole demonstrated non-inferiority in clinical cure rates at the test of cure
(TOC) visit compared with vancomycin monotherapy and vancomycin/ceftazidime in STRAUSS I
and II trials, respectively [50]. More recently, in a phase III, randomized, double-blind, comparative
(NCT00326287) study comparing ceftobiprole medocaril to ceftriaxone/linezolid for CABP, ceftobiprole
achieved a cure rate of 76.4% compared with that of 79.3% for ceftriaxone/linezolid [95% CI: −9.3%
to 3.6%] while both drugs being well tolerated [51]. In another randomized double-blind phase III
trial (NCT00210964/NCT00229008), ceftobiprole medocaril was compared to ceftazidime/linezolid for
hospital-acquired pneumonia (HAP) including ventilator-associated pneumonia (VAP) [52]. The cure
rate for ceftobiprole was 49.9% compared to that of 52.8% in ceftazidime/linezolid [95% CI: −10% to
Microorganisms 2019, 7, 270 7 of 24

4.1%] with similar adverse event rates at 24.9% and 25.4% respectively, displaying non-inferiority [52].
However, in VAP patients, ceftobiprole did not demonstrate non-inferiority in terms of both the cure
rate and microbiological eradication rate compared with ceftazidime/linezolid [52].
The most commonly (≥3% of patients) reported adverse reactions of ceftobiprole were nausea
(4%), diarrhea (4.2%), neutropenia (4.0%) and drug hypersensitivity reactions including urticaria and
pruritic rash (3.0–9.3%) [14,53,54].
Recently a phase III non-inferiority clinical trial (TARGET study, NCT03137173) that compared
ceftobiprole with vancomycin plus aztreonam for ABSSSI, was completed [55]. On 6th of August 2019
positive topline results were announced: the primary endpoint that was early clinical response was
met (91.3% for ceftobiprole versus 88.1% for vancomycin plus aztreonam) [55]. The two secondary
endpoints of clinical success at TOC visits (days 15 to 22) were met as well, for both the intention-to-treat
(ITT) population (90.1% versus 89%) and the clinically evaluable population (97.9% versus 95.2%) [56].
Ceftobiprole was tolerated well and the adverse events were similar between ceftobiprole and
comparator (20% versus 18%, respectively) [56].
Ceftobiprole was approved by EMA in October 2013 for the indications of HAP (excluding VAP)
and CABP [56]. Treatment may continue in patients with HAP who subsequently deteriorate and
require mechanical ventilation. It is marketed in many European countries as well as several other
countries, such as Canada and Argentina [56]. Ceftobiprole has also received Qualified Infectious
Disease Product (QIDP) designation from the FDA for S. aureus bacteremia (SAB), ABSSSI and CABP
in the United States [56]. A phase III trial evaluating the safety and efficacy of ceftobiprole medocaril
compared with daptomycin in treating SAB, including infective endocarditis, is currently recruiting
and is expected to be completed in August 2021 (ERADICATE study, NCT03138733) [57]. ERADICATE
study along with TARGET study are both under a Special Protocol Agreement with FDA [56].
Ceftobiprole represents an effective and well-tolerated addition to the antimicrobial
armamentarium for the empirical treatment of HAP patients (but not for VAP patients). Due to
its broad-spectrum of activity, it provides a promising monotherapy alternative to the combination
therapy. However, more studies are needed to further assess the activity of ceftobiprole in MRSA HAP
against comparators, i.e., linezolid or vancomycin.

2.2. Glycopeptides

2.2.1. Dalbavancin
Dalbavancin (trade name Dalvance in US, Xydalba in Europe), developed by Durata Therapeutics
(acquired by Actavis in 2014), is a semisynthetic lipoglycopeptide. Its mechanism of action is similar to
vancomycin, which consists of binding to D-alanyl-D-alanine terminus of the stem pentapeptide in
peptidoglycan, thereby preventing cross-linking of cell wall synthesis [58]. However, dalbavancin has
an additional lipophilic side chain that anchors it to the cellular membrane, allowing it to have enhanced
activity and four to eight times the potency of vancomycin [58,59]. Dalbavancin’s in vitro spectrum of
antibacterial activity covers MRSA, S. pyogenes, S. agalactiae, Streptococcus anginosus group (including
S. anginosus, S. intermedius, and S. constellatus), and E. faecalis strains susceptible to vancomycin [60].
It is important to note enterococcal species with Van-A phenotype expression have resistance against
dalbavancin [58].
The half-life of dalbavancin is approximately 8.5 days, allowing it to be administered once-weekly
in a two-dose regimen [59,61–63]. It has high plasma protein binding (average 93%; mainly albumin)
that is concentration independent and not affected by renal or hepatic insufficiency [16]. Dalbavancin’s
mean plasma clearance decreases and area under the curve increases in patients with creatinine
clearance below 30 mL/min, requiring dosage reduction [64]. It is administered by IV infusion over
30 min [60].
DISCOVER I and DISCOVER II are two identically designed, randomized, double-blind,
double-dummy phase III trials comparing the efficacy and safety of dalbavancin to vancomycin and
Microorganisms 2019, 7, 270 8 of 24

linezolid for the treatment of ABSSSIs (NCT01339091 and NCT01431339), and both studies demonstrated
that IV dalbavancin 1000 mg on day 1 and 500 mg on day 8 is non-inferior to IV vancomycin (1 g
every 12 h or 15 mg/kg every 12 h) with optional switch to oral linezolid (600 mg every 12 h) for
10–14 days [61]. The three commonest adverse effects from both treatment groups of dalbavancin and
vancomycin-linezolid were nausea, diarrhea, and pruritus [61]. Infusion site-related reactions and
flushing occurred less frequently in the dalbavancin group compared to the vancomycin-linezolid
group (1.4% vs. 1.7% and 0.2% vs. 0.6%, respectively) [61]. A randomized, double-blind phase III
trial (NCT02127970) in patients with ABSSSIs found that a single dose of dalbavancin 1500 mg by IV
infusion is non-inferior to the two-dose regimen in reducing >20% of erythematous area at 48–72 h
(81.4% vs. 84.2%; difference, −2.9% [95% CI, −8.5% to 2.8%]), as well as non-inferior clinical outcomes
on day 14 and day 28 [65]. The frequency of treatment-emergent adverse events was similar in both
groups [65].
In 2014, dalbavancin was approved for treating ABSSSIs in adults by both the FDA and the
EMA [16,66]. To date, there is one phase III trial currently recruiting participants to compare
dalbavancin for treating ABSSSIs in children aged three months to 17 years of age (NCT02814916) [67].
There are currently five phase IV clinical trials (two completed but pending results (NCT02940730
and NCT03233438), two recruiting participants (NCT03426761 and NCT03372941) and one not yet
recruiting (NCT03982030)). The two completed studies evaluate the pharmacokinetic properties of
dalbavancin in patients undergoing chronic peritoneal dialysis (NCT02940730), the other one entails the
comparison of a New Critical Pathway using dalbavancin versus the standard of care in clinical practice
for ABSSSIs treatment (NCT03233438) [68,69]. A phase III trial of dalbavancin in CABP sponsored by
the manufacturer (NCT02269644) has been withdrawn prior to enrolment [70]. Data regarding the
intrapulmonary pharmacokinetics of dalbavancin are scarce [71].
Due to its long half-life and, thus, weekly administration dosing scheme, dalbavancin has a very
promising potential to decrease the duration of hospital stay and for use in the Outpatient Parenteral
Antibiotic Therapy population, especially for vulnerable and/or patients with poor adherence to
medications [72,73].

2.2.2. Oritavancin
Oritavancin (trade name Orbactiv), developed by Melinta Therapeutics, Inc., is a new-generation
lipoglycopeptide derived from chloroeremomycin, an analogue of vancomycin [74]. Oritavancin
has rapid bactericidal activity against Gram-positive bacteria, including MSSA, MRSA, VRE and
vancomycin-intermediate and vancomycin-resistant staphylococci [74]. Unlike its precursors,
oritavancin disrupts the bacterial membrane integrity leading to the bactericidal killing of Gram-positive
pathogens [75]. It also appears to inhibit bacterial RNA synthesis [74]. The spectrum of activity is similar
to vancomycin, but with a lower MIC (MIC90 of 0.008 µg/mL against S. pneumoniae, MIC90 of 0.12 µg/mL
against E. faecium isolates, and MIC90 of 0.2 µg/mL against S. aureus) [76]. In vitro, oritavancin has
activity against Enterococcus isolates with Van-A (MIC: >4 mg/L vancomycin & >8 mg/L teicoplanin)
and Van-B ((MIC: >4 mg/L vancomycin & ≤8 mg/L teicoplanin) phenotypes (while the other novel
members of the class, i.e., dalbavancin & telavancin, have activity only against Van-B [77].
The unique lipophilic side-chain of oritavancin prolongs the half-life compared to vancomycin
(terminal half-life >10 days, the longest of the glycopeptide class), allowing for single-dose
treatment [17,78]. Oritavancin has high plasma protein binding (average 80%) and is eliminated
from tissue sites at a slow rate, with no dose adjustments required for mild to severe renal or moderate
hepatic insufficiency or other subpopulations including age, gender, race and weight [78–80].
Two identical, multi-center, randomized non-inferiority phase III trials, SOLO I and SOLO II,
compared the efficacy and safety of a single dose of 1200 mg oritavancin IV oritavancin versus
vancomycin IV (1 g or 15 mg/kg) twice daily for 7–10 days in adults with ABSSSI due to proven or
suspected Gram-positive pathogens [17,81]. The initial protocol required patients to be hospitalized
until the early clinical assessment (48–72 h after treatment initiation), the protocol was amended
Microorganisms 2019, 7, 270 9 of 24

to include the entire treatment at outpatient setting based on the investigator’s discretion [82].
Although efficacy response rates and the incidence of adverse events were similar for oritavancin
and vancomycin, oritavancin provides a single-dose alternative to multi-dose vancomycin for the
treatment of ABSSSI [17,82]. A post-hoc analysis of the subgroup of patients that received the entire
treatment course in an outpatient setting also concluded that oritavancin and vancomycin had similar
efficacy [82].
The most commonly reported adverse reactions in pooled ABSSSI clinical trials for oritavancin
compared to vancomycin were headache (7.2% vs. 7.9%), nausea (11.0% vs. 8.9%) and vomiting (4.9%
vs. 3.7%), diarrhea (4.9% vs. 3.5%), limb and abscess limb (2.8% vs. 1.6%), however treatments were
rarely discontinued [17,79,83,84]. The high intracellular accumulation of oritavancin suggests potential
toxicity in tissues, such as the liver and lungs, therefore close monitoring is required to determine the
side effects until more clinical data is available [83,85].
In August 2014 and March 2015, the FDA and EMA, respectively, approved oritavancin for the
treatment of ABSSSI due to MSSA, MRSA, Streptococcus spp., and E. faecalis in adults administered
via IV infusion of 1200 mg single dose over three hours [74,79,80,86]. Despite potent antimicrobial
activity, oritavancin has not been clinically evaluated against VRE. A multi-center phase I clinical trial
is currently recruiting participants to evaluate the safety and tolerability of IV oritavancin in pediatric
patients (<18 years old) with Gram-positive bacterial infections (NCT02134301) [87]. Another phase
IV clinical trial, estimated to be completed by the end of 2019, is evaluating the safety and efficacy
of oritavancin in adult patients with a systemic infection of S. aureus, namely bacteremia or infective
endocarditis (NCT03761953) [88].
A single dose of oritavancin due to its long half-life, along with its safety profile, makes it a very
promising option for effectively shifting inpatient to outpatient setting care for patients with ABSSSI
and, thus, substantially decreasing the related healthcare costs. Future studies are needed, however,
to evaluate the role of oritavancin in the treatment of enterococcal infections.

2.2.3. Telavancin
Telavancin (trade name Vibativ), developed by Theravance Biopharma Antibiotics, Inc.,
is a lipoglycopeptide antibiotic with rapid bactericidal activity against both aerobic and
anaerobic Gram-positive bacteria, including MRSA, vancomycin-intermediate S. aureus (VISA) and
penicillin-resistant S. pneumoniae [89–91]. It is a semi-synthetic derivative of vancomycin whose dual
mechanism of action involves inhibiting cell wall synthesis of peptidoglycan chain and disrupting
membrane barrier function by dissipating its potential [92].
Telavancin has a high plasma protein binding (average 90%; mainly with albumin) and an average
half-life of 8 h [15]. Its main route of elimination is renal excretion and dose adjustment is needed in
cases with renal impairment [15] Telavancin has good penetration in the ELF and alveolar macrophages
of healthy subjects, resulting in concentrations 8 to 85-fold above MIC90 of MRSA strains [91]. In vitro,
telavancin is not deactivated by the presence of the alveolar surfactant but remains active [91].
Two identical, randomized phase III trials were conducted to compare telavancin (10 mg/kg IV
every 24 h) and vancomycin (1 g IV every 12 h) for the treatment of cSSSI due to MRSA (NCT00091819
(ATLAS1), NCT00107978 (ATLAS2)) [15,93]. In patients with MRSA infections, cure rates were 91%
when treated with telavancin and 86% when treated with vancomycin [94]. Cure rates for telavancin
and vancomycin treatment arms were comparable (88.3% vs. 87.1%) [94]. Adverse events that resulted
in discontinuation of therapy occurred in 8% and 6% when treated with telavancin and vancomycin
respectively [94]. When given once daily, telavancin is at least as effective as vancomycin for cSSSI,
including infections caused by MRSA [94]. Adverse events were similar between groups in terms of
type and severity, however mild taste disturbance, nausea and vomiting and elevated serum creatinine
concentration was apparent in the telavancin group, whilst pruritus occurred in the vancomycin
treatment [94].
Microorganisms 2019, 7, 270 10 of 24

Another two identical, randomized, double-blind phase III non-inferiority studies (NCT00107952
[ATTAIN1], NCT00124020 [ATTAIN2])) compared the safety and effectiveness of telavancin with
vancomycin for the treatment of HAP in adult patients [89]. Telavancin resulted in higher cure rates
for S. aureus infections than vancomycin, and comparable cure rates in MRSA infections [89]. However,
vancomycin achieved higher cure rates in patients with mixed Gram positive and Gram-negative
infections [89]. Mortality rates for telavancin and vancomycin-treated patients were dissimilar in the
two studies, but there was no statistical significance in either of them: 21.5% vs. 16.6% (95% CI for
the difference, −0.7% to 10.6%) for the NCT00107952 and 18.5% vs. 20.6% (95% CI for the difference,
−7.8% to 3.5%) for the NCT00124020 [89]. Telavancin resulted in increased serum creatinine levels
more frequently (16% vs. 10%) compared to the vancomycin group, nevertheless, incidence and
types of other adverse events, such as anemia, abnormal serum potassium levels and hepatic enzyme
abnormalities, were comparable between the two groups of ATTAIN studies [89]. Baseline renal
status should be considered before treatment initiation, while renal function monitoring is necessary
for all patients on telavancin [89]. Moreover, it should be noted that the effectiveness of telavancin
appears to be lower in patients with pre-existing moderate renal impairment (creatinine clearance
<50 mL/min) [95].
The FDA approved telavancin for its use in cSSSI in September 2009 and in June 2013, approved
its use in HAP and VAP caused by S. aureus. Telavancin has been withdrawn from use in the European
Union due to insufficient data to conclude a positive benefit-risk balance for use in cSSSI in adults [96].
Phase IV studies involving the pharmacokinetics of telavancin use in cystic fibrosis (NCT03172793)
and pediatric patients (NCT02013141) are currently recruiting and are estimated to be completed in
mid-2019 and December 2020, respectively.
The rapid bactericidal activity, including VISA strains, along with its favorable pharmacokinetic
characteristics (high protein-binding, long half-life, post-antibiotic effect), makes telavancin a promising
antibacterial agent that complements the armamentarium against HAP and VAP from Gram-positive
pathogens, especially MRSA. More studies are warranted to evaluate further indications of telavancin
and its future role in the clinical setting.

2.3. Oxazolidinones

Tedizolid Phosphate
Tedizolid Phosphate (formerly torezolid, trade name Sivextro), developed by Cubist
Pharmaceuticals, is a novel phosphate ester prodrug of tedizolid, an oxazolidinone-class antibiotic [97].
Tedizolid, exerts bacteriostatic activity by binding to the 23S ribosomal RNA (rRNA) of the 50S subunit
of the bacterial ribosome and thus inhibiting protein synthesis [24]. Compared to linezolid which has
a similar mechanism of action, it binds stronger to the active site due to its unique D-ring substituent
providing additional hydrogen bonds [24].
In vitro studies have found that tedizolid has high antibacterial activity against Gram-positive
microorganisms resistant to commonly used antibiotics, such as linezolid and methicillin [98].
The unique D-ring and a hydroxymethyl group has important contribution to tedizolid’s activity
against linezolid-resistant strains [24]. It should be noted, however, that although tedizolid
is active against linezolid-resistant pathogens with plasmid-borne and transposon associated
chloramphenicol-florfenicol resistance (cfr) gene, it has cross-resistance to linezolid when mutations
in chromosomal genes encoding 23S rRNA or ribosomal proteins (L3 and L4) are present [99,100].
One study showed that the antibacterial activity of tedizolid was four to eight times higher than linezolid
with 302 MRSA strains and 220 vancomycin-intermediate Enterococcus spp. Strains [101]. Overall,
tedizolid maintained a potent level of activity against target pathogens, especially staphylococci [101].
This increased potency allows for once daily dosing with reduced total dosages. Only 13 of 6884
strains had a tedizolid MIC values ≥1 µg/mL, whilst 99.8% of isolates were inhibited at MIC values
≤0.5 µg/mL [89,102]. Similarly, in neutropenic mouse thigh models of MSSA and MRSA infections,
Microorganisms 2019, 7, 270 11 of 24

tedizolid demonstrated potent activity against one MSSA strain and two MRSA strains, outperforming
linezolid in each case [90,103]. The study concluded that tedizolid demonstrated superiority in
microbiological effect relative to linezolid even after MIC, protein binding and pharmacokinetics were
adjusted for [103].
The phosphate group of tedizolid’s prodrug increases its bioavailability by increasing its water
solubility [24]. Thus, following oral or intravenous administration, tedizolid phosphate is rapidly
converted by endogenous phosphatases to tedizolid [24]. Tedizolid accumulates in macrophages of
the peripheral blood and of the alveoli [24]. It also has extensive penetration into both extracellular
and intracellular pulmonary compartments resulting in higher concentrations (>20-fold) in the ELF
and alveolar macrophages compared to free plasma concentrations [24,104]. Studies performed in
obese patients, patients with any degree of renal failure or liver failure and those over 65 years of
age, demonstrated similar pharmacokinetics and no difference in adverse events, therefore no dose
adjustment is required, even though approximately 35% is excreted by the kidneys [105].
Two pivotal phase III trials were conducted to compare the safety profiles of tedizolid phosphate
to linezolid in the treatment of ABSSSI [106]. ESTABLISH-1, a randomized, double-blind, multi-center
phase III trial was conducted in 667 adults ≥18 years of age with ABSSSI (NCT01170221) [106]. Tedizolid
phosphate was found to be statistically non-inferior to linezolid in the early stages of clinical response (48
to 72 h) after therapy commencement [106]. The overall incidence of serious adverse events was similar
after a 10-day course of either tedizolid phosphate and linezolid [106]. ESTABLISH-2, a randomized,
double-blind, non-inferiority phase III trial investigating the use of tedizolid for six days versus linezolid
for 10 days was conducted in patients ≥12 years of age with ABSSSI [107]. Similar to results from
ESTABLISH-1, tedizolid achieved early clinical response and reached the prespecified non-inferiority
margin [107]. Moreover, the tedizolid group experienced less frequent gastrointestinal adverse events
than the linezolid group, and one patient in the tedizolid group experienced a treatment-emergent
adverse event versus four patients in the linezolid group [107]. The most common adverse reactions
(>2%) occurring in patients treated with tedizolid were nausea (8%), headache (6%), diarrhea (4%),
vomiting (3%), and dizziness (2%) [18]. Tedizolid may have lower hematologic toxicity compared with
linezolid. In the ESTABLISH 1 & 2 trials, thrombocytopenia was observed in 2.3% of the tedizolid
treated patients, compared with 4.9% of the linezolid treated patients [106]. However, this finding may
reflect the shorter tedizolid dosing regimen used in these trials [106]. As the number of patients treated
with tedizolid increases, the assessment of thrombocytopenia should be investigated with real-world
safety studies [108].
Tedizolid phosphate was approved by the FDA in June 2014 for the treatment of adult patients
with ABSSSI [109,110]. It was also approved by the EMA in March 2015 for the same indication [110].
A phase III non-inferiority trial (NCT02019420) that compared tedizolid with linezolid for the treatment
of Gram-positive ventilated nosocomial pneumonia was completed in June 2018 and results are
pending [111]. The two study groups received either tedizolid 200 mg IV once daily for 7 days (or 14
for concurrent bacteremia) or linezolid 600 mg IV twice daily for 10 days (or 14 days for concurrent
bacteremia and the primary outcome was 28-day all-cause mortality [111]. Currently, a phase I clinical
trial (NCT03217565) determining the single-dose pharmacokinetics of IV and oral tedizolid phosphate
in pediatric participants with Gram-positive infections started in February 2019 and is expected to be
completed in July 2021 [20]. Another randomized phase III trial (NCT03176134) evaluating the safety,
tolerability and efficacy of tedizolid phosphate versus a comparator agent in participants <12 years of
age with ABSSSI started in January 2019 and is expected to be completed in September 2021 [20].
Tedizolid is the first oxazolidinone administered only once-daily. The convenient dosing scheme,
the lack of need for dose adjustment when switching from IV to oral administration, along with its
action against linezolid-resistant strains and the lower frequency of thrombocytopenia, makes tedizolid
a promising antibacterial agent against severe infections from Gram-positive pathogens. However,
further assessment is needed of thrombocytopenia development in the clinical setting.
Microorganisms 2019, 7, 270 12 of 24

2.4. Quinolones

2.4.1. Besifloxacin
Besifloxacin (trade name Besivance), developed by SSP Co. Ltd. and sold to Bausch &
Lomb in 2003, is a fluoroquinolone antibiotic that was approved by the FDA in May 2009 for
bacterial conjunctivitis [112]. Similar to other fluoroquinolones, besifloxacin’s mechanism of
action involves inhibition of DNA topoisomerases including DNA gyrase and topoisomerase IV,
thereby inhibiting DNA synthesis [113]. Besifloxacin exhibits greater in vitro activity against both
enzymes in S. pneumoniae compared to moxifloxacin and ciprofloxacin [112]. Besifloxacin has
a wide spectrum of antibacterial activity that covers Gram-positive, Gram-negative and anaerobic
organisms [112,114,115]. It demonstrates particularly more rapid in vitro bactericidal effects on
the common ocular pathogens S. aureus, S. epidermidis, S. pneumoniae, and Haemophilus influenzae
compared to moxifloxacin and gatifloxacin [112,114,115]. The Antibiotic Resistance Monitoring in
Ocular microorganisms (ARMOR) study in the United States found that besifloxacin exhibited the
lowest MIC90 against staphylococcal (including methicillin-resistant isolates) and streptococcal isolates
among fluoroquinolones, with a MIC90 comparable to vancomycin for MRSA [116]. Multiple studies
showed that the emergence of besifloxacin-resistant S. aureus and S. pneumoniae occurred at a much
lower rate than other fluoroquinolones due to its non-preferential binding for both DNA gyrase and
topoisomerase IV, resulting in a reduced risk for spontaneous resistance [117–119].
Besifloxacin is available as a 0.6% (6 mg/mL) ophthalmic suspension and is approved for topical
ophthalmic use for bacterial conjunctivitis in patients with an age of one year and older [120].
The commonest adverse effects include blurred vision, eye pain, eye irritation, conjunctival redness,
and eye pruritus (1.1–2.1% incidence) [121]. In regard to the safety and efficacy of besifloxacin in
neonates, a phase III, small, multi-center, randomized, double-masked, parallel clinical trial (n = 33)
found that both besifloxacin and gatifloxacin were safe and effective in treating neonatal bacterial
conjunctivitis, with besifloxacin demonstrating earlier bacterial eradication with no adverse events
reported [122]. The commonest adverse event associated with besifloxacin for topical ophthalmic use
is conjunctival redness (2%) [19].

2.4.2. Delafloxacin
Delafloxacin (trade name Baxdela), developed by Melinta Therapeutics Inc., is a novel
fluoroquinolone which inhibits DNA gyrase and topoisomerase IV [20,123]. Its distinct chemical
structure confers to delafloxacin a weakly acidic character that results in increased cellular penetration as
well as increased bactericidal activity in the acidic environment of the infection site [124]. This enhanced
antibacterial activity is contrary to the characteristics of the other members of the class that demonstrate
decreased activity in acidic environments [124]. Moreover, compared to the other fluoroquinolones,
delafloxacin exerts a more balanced inhibition of both DNA gyrase and topoisomerase IV that should
theoretically decrease resistance selection [124].
Delafloxacin covers a broad-spectrum of Gram-positive pathogens, including S. aureus (including
MRSA and MSSA isolates), S. pneumoniae, and most fluoroquinolone-resistant strains except
enterococci [20,123]. Delafloxacin also has good antimicrobial activity against Enterobacteriaceae,
but its activity against P. aeruginosa is weaker compared to that of ciprofloxacin. In vitro studies
have shown that delafloxacin is highly potent against fluoroquinolone-susceptible S. aureus with
a MIC50 of 0.004 mg/l compared to that of levofloxacin (0.25 mg/L) and moxifloxacin (0.06 mg/L),
and fluoroquinolone-resistant S. aureus with a MIC50 of 0.25 mg/l compared to that of levofloxacin
(16 mg/L) and moxifloxacin (4 mg/L) [125]. Another in vitro study found that the MIC50 of delafloxacin
was 4- to 64-fold lower than that of ciprofloxacin, levofloxacin and moxifloxacin against 30 clinical MRSA
strains [126]. In murine neutropenic lung infection models, delafloxacin showed significantly lower MIC
against MRSA, MSSA and S. pneumoniae, when compared with azithromycin and levofloxacin [127].
Microorganisms 2019, 7, 270 13 of 24

Delafloxacin has high plasma protein binding (average 83%, mainly albumin) [124]. It is
eliminated via the kidneys, therefore adjustment for intravenous dosing is required in patients with
renal impairment but not hepatic impairment [128]. The bioavailability of delafloxacin oral formulation
is 58.8%, with a volume of distribution of 30–48 L, a mean half-life of 3.7 h and liver glucuronidation as
its primary metabolic pathway [20]. Delafloxacin, similarly to the other members of fluoroquinolone
class, has high lung penetration with 13:1 ELF to free plasma concentration [124].
In one multi-center, randomized, double-blind phase II study (NCT00719810), delafloxacin was as
effective as tigecycline for cSSSIs and was well tolerated [129]. In another randomized, double-blind
phase II study (NCT01283581), delafloxacin demonstrated significantly higher clinical cure rates
than vancomycin (mean difference −16.3%, 95% CI: −30.3% to −2.3%) against ABSSSIs caused by all
clinical isolates except MRSA, in which cure rates for delafloxacin were comparable to vancomycin or
linezolid [130]. In a multi-center, randomized, double-blind phase III study (NCT01984684), IV/oral
monotherapy delafloxacin was non-inferior to IV vancomycin/aztreonam in patients with ABSSSIs,
including those with MRSA infections, with the percentage of patients achieving ≥20% reduction in
erythema area of the lesion being 83.7% versus 80.6% (95% CI −2.0 to 8.3%) at 48 to 72 h [131].
Its common side effects (≥2% incidence), similar to other fluoroquinolones, include tendinitis,
tendon rupture, arthralgia, myalgia, peripheral neuropathy, and central nervous system effects including
hallucinations, anxiety, depression, insomnia, severe headaches, and confusion [20]. Other more
serious adverse reactions that led to study discontinuation include urticaria (0.3%) and hypersensitivity
(0.3%) [20]. Although the available clinical evidence is rather limited, delafloxacin appears to be better
tolerated compared with other commonly used fluoroquinolones [132].
Delafloxacin was approved by the FDA for the treatment of ABSSSIs in adults in June 2017 [133].
Melinta Therapeutics also submitted a Marketing Authorization Application (MAA) to the EMA for
the same indication in March 2018 [134]. A multi-center, randomized, double-blind phase III study
(DEFINE-CABP, NCT02679573) comparing delafloxacin to moxifloxacin for treating adults with CABP
was completed in 2018 with results pending, while Melinta Therapeutics had submitted an NDA to the
FDA for the indication for CABP in the same year [135,136]. Delafloxacin has received QIDP from
FDA for cUTI [136].
The enhanced intracellular penetration and bactericidal activity in acidic environments, along with
the dual mechanism of action that limits resistance development, makes delafloxacin a promising
treatment for ABSSSIs, and in the future, depending on trials results, potentially for CABP.

2.4.3. Ozenoxacin
Ozenoxacin (trade name Ozaenex/Xepi), developed by Ferrer International S.A., is a novel,
non-fluorinated, topical quinolone that is bactericidal against many Gram-positive organisms, including
MRSA, MSSA, MRSE and S. pyogenes [137]. In vitro, MIC90 values against bacteria such as MSSA,
MRSA, S. epidermis was between two- and >16,000-fold greater than compared to other commonly
prescribed antibiotics, such as ofloxacin, levofloxacin, erythromycin and gentamicin [138]. Previous
trials demonstrated a complete lack of systemic absorption and no formation of metabolites when
ozenoxacin was applied topically, likely contributing to the absence of drug interactions [137]. As a result,
the elimination of ozenoxacin has not been investigated in humans [139]. Previous studies conducted to
determine the toxicity of orally administered ozenoxacin have demonstrated non-toxicity in the brain,
thymus, liver, lungs and kidney after adequate systemic exposure in juvenile dogs [140]. Furthermore,
no dose adjustment is required for geriatrics or people with hepatic and renal impairment [139].
The FDA approved ozenoxacin in November 2017 for the treatment of impetigo caused by S.
aureus and S. pyogenes in both adults and pediatric patients older than two months of age [21,137].
This was based on two multi-center, randomized, phase III clinical trials evaluating the safety and
efficacy of ozenoxacin cream in patients with non-bullous or bullous impetigo (NCT01397461 and
NCT02090764) [137]. Ozenoxacin demonstrated superior clinical success compared to the placebo after
five days of therapy and superior microbiological success after two days of therapy [141]. Ozenoxacin
Microorganisms 2019, 7, 270 14 of 24

was well tolerated with only one of 206 patients experiencing rosacea and seborrheic dermatitis which
was not considered a serious adverse event [141].

2.5. Tetracyclines

Omadacycline
Omadacycline (trade name Nuzyra), developed by Paratek Pharmaceuticals, is a tetracycline
antibiotic belonging to the aminomethylcycline subclass, with improved oral bioavailability compared
to tigecycline, and its antibacterial profile and efficacy are superior to the earlier members of the class,
such as tetracycline, doxycycline, and minocycline [142]. Omadacycline binds to the 30S ribosomal
subunit and inhibits protein synthesis and is active against certain antibiotic resistance mechanisms such
as tetracycline efflux and ribosome protection [143]. In vitro, omadacycline is active against bacteria
associated with ABSSSIs and CABP including MRSA, penicillin-resistant and multidrug-resistant S.
pneumoniae, and vancomycin-resistant Enterococcus spp. [144]. It also has a broad range of activity
against Gram-negative bacteria, with the main exclusion of P. aeruginosa.
Omadacycline has low plasma protein binding and a half-life of approximately 16–17 h,
which supports once daily dosing scheme [25]. It is eliminated via the kidneys but does not require
dose adjustment in either kidney or liver impairments [22]. Omadacycline has demonstrated good
lung penetration with the ratio of ELF and alveolar cells to total plasma concentrations being 1.47 and
25.8 respectively, compared with those of tigecycline (1.71 and 20.8, respectively) [145].
A phase II study indicated that omadacycline was well-tolerated and effective against cSSSIs
compared with linezolid [146]. A phase III study (NCT02378480) demonstrated that omadacycline
was effective and non-inferior to linezolid for the treatment of ABSSSIs (rate of early clinical response
84.8% vs. 85.5%, respectively), and was generally safe and well-tolerated following both IV and oral
dosing, with a similar safety profile to linezolid (adverse events 48.3% in the omadacycline group
vs. 45.7% in the linezolid group, respectively; with gastrointestinal being the most frequent in both
groups) [147–149]. Rates of clinical response at the post-treatment evaluation were similar in the
omadacycline and linezolid groups among patients with monomicrobial gram-positive infections (87.8%
and 84.8%, respectively), polymicrobial gram-positive infections (74.2% and 81.5%), and polymicrobial
mixed infections (80.5% and 75.9%). Clinical response at the post-treatment evaluation in the small
subgroup of patients with bacteremia occurred in 82% of patients (9 of 11) who received omadacycline
and 100% of patients (9 of 9) who received linezolid. In both groups, the efficacy of omadacycline and
linezolid against MRSA (83 vs. 86%, respectively) and MSSA (84 vs. 82%, respectively) infections
were similar [149]. Another phase III study (NCT02531438) found that oral omadacycline was safe,
well-tolerated and non-inferior to moxifloxacin in treating CABP with a clinical success rate of 92.9%
versus 90.4% (95% CI: −1.7 to 6.8) [150]. Omadacycline demonstrated non-inferiority to moxifloxacin
for early clinical response (83.1% vs. 82.7%, respectively) [151]. The analysis of the microbiologic ITT
population also resulted in similar clinical response rates (89.2% and 87.4%), while similar efficacy
in the two treatment groups was observed within subgroups based on Pneumonia Severity Index
(PSI) risk class [151]. With regards to adverse events after treatment initiation, omadacycline had
41.15% compared to 48.5% of moxifloxacin group, with gastrointestinal events being the most frequent
(10.2% vs. 18.0%, respectively (the largest difference was in the incidence of diarrhea, i.e., 1.0% vs.
8.0%, respectively) [151]. Although eight deaths occurred in the omadacycline group and four in
the moxifloxacin group, these all occurred in patients older than 65 years of age and were due to
progression of the underlying pneumonia or respiratory compromise, cardiac or vascular events and
cancer [151].
In October 2018, the FDA approved omadacycline for the indications of CABP and ABSSSIs in
both IV and tablet formulations [22]. The submission of the MAA from Paratek Pharmaceuticals was
also accepted in the same month by the EMA [152]. A phase II study (NCT03425396) that compared
per os administration of omadacycline versus nitrofurantoin for cystitis and uncomplicated UTI,
Microorganisms 2019, 7, 270 15 of 24

was very recently completed and topline data are expected to be announced in the second half of
2019 [152]. Another phase II clinical trial (NCT03757234) testing omadacycline (IV or IV/PO) efficacy
versus levofloxacin (IV/PO) in treating acute pyelonephritis is expected to be completed in September
2019 [153].
With a very wide anti-bacterial spectrum, minimal drug-drug interaction, a favorable safety
profile and the availability of both IV and oral formulations, omadacycline seems to be a promising
alternative for the treatment of CABP and ABSSSI, while further studies will evaluate its clinical role
for further indications.

3. Conclusions
Increasing multidrug-resistance to Gram-positive pathogens, particularly those caused by MRSA,
VRE and S. pneumoniae, has become a major problem in hospital environments, resulting in significant
morbidity and mortality [154]. As antibiotics are rendered resistant to bacteria, this leads to the overuse
of empiric therapy as well as the need to resort to potentially more toxic agents [154].
The antimicrobial agents discussed above are highly significant in the treatment of MDR infections,
however, as for any emerging antibiotic agent, resistance is likely to develop. Only through appropriate
dosing, utilization and careful monitoring for the emergence of antimicrobial resistance can these
current antimicrobial drugs continue to treat Gram-positive pathogens in the future [155]. Future
trials should be conducted to investigate these drugs for further indications of use and unanticipated
adverse effects.

Supplementary Materials: The following are available online at http://www.mdpi.com/2076-2607/7/8/270/s1,

Figures S1–S10: Chemical structures.
Funding: This research received no external funding.
Conflicts of Interest: Author J.L. reports: Advisory Board with Bayer and MSD and honorarium for lectures from
Pfizer and MSD. All other authors (DK, EX, AS, IYSM, DEK, AA and ST) declare no competing interests.

Abbreviations
ABSSSI (Acute Bacterial Skin and Skin Structure Infection), CABP (community-acquired bacterial pneumonia),
cSSSI (complicated skin and skin structure infection), EMA (European Medicine Agency), FDA (Federal Drug
Administration), HAP (hospital-acquired pneumonia), IV (intravenous), PO (per oral), VAP (ventilator-associated
pneumonia).

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